Multiple organic anion transporters contribute to net renal excretion of uric acid
- 1 April 2008
- journal article
- research article
- Published by American Physiological Society in Physiological Genomics
- Vol. 33 (2), 180-192
- https://doi.org/10.1152/physiolgenomics.00207.2007
Abstract
Excretion of uric acid, a compound of considerable medical importance, is largely determined by the balance between renal secretion and reabsorption. The latter process has been suggested to be principally mediated by urate transporter 1 (URAT1; slc22a12), but the role of various putative urate transporters has been much debated. We have characterized urate handling in mice null for RST, the murine ortholog of URAT1, as well as in those null for the related organic anion transporters Oat1 and Oat3. Expression of mRNA of other putative urate transporters (UAT, MRP2, MRP4, Oatv1) was unaffected in the knockouts, as were general indexes of renal function (glomerular filtration rate, fractional excretion of fluid and electrolytes). While mass spectrometric analyses of urine and plasma revealed significantly diminished renal reabsorption of urate in RST-null mice, the bulk of reabsorption, surprisingly, was preserved. Oat1- and Oat3-null mice manifested decreased secretion rather than reabsorption, indicating that these related transporters transport urate in the “opposite” direction to RST. Moreover, metabolomic analyses revealed significant alteration in the concentration of several molecules in the plasma and urine of RST knockouts, some of which may represent additional substrates of RST. The results suggest that RST, Oat1, and Oat3 each contribute to urate handling, but, at least in mice, the bulk of reabsorption is mediated by a transporter(s) that remains to be identified. We discuss the data in the context of recent human genetic studies that suggest that the magnitude of the contribution of URAT1 to urate reabsorption might vary with ethnic background.Keywords
This publication has 68 references indexed in Scilit:
- Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin GAmerican Journal of Physiology-Renal Physiology, 2007
- Mobilization of pro-inflammatory lipids in obese Plscr3-deficient miceGenome Biology, 2007
- Homozygous frameshift mutation in the SLC22A12 gene in a patient with primary gout and high levels of serum uric acidJournal of Clinical Pathology, 2006
- Unearthing uric acid: An ancient factor with recently found significance in renal and cardiovascular diseaseKidney International, 2006
- XCMS: Processing Mass Spectrometry Data for Metabolite Profiling Using Nonlinear Peak Alignment, Matching, and IdentificationAnalytical Chemistry, 2006
- Novel slc22 transporter homologs in fly, worm, and human clarify the phylogeny of organic anion and cation transportersPhysiological Genomics, 2004
- The Molecular Pharmacology of Organic Anion Transporters: from DNA to FDA?Molecular Pharmacology, 2004
- A Novel Putative Transporter Maps to the Osteosclerosis (oc) Mutation and Is Not Expressed in theocMutant MouseGenomics, 1999
- Molecular Cloning and Characterization of NKT, a Gene Product Related to the Organic Cation Transporter Family That Is Almost Exclusively Expressed in the KidneyPublished by Elsevier BV ,1997
- Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis.Proceedings of the National Academy of Sciences of the United States of America, 1981